With rapid progress in human genomics and identification of disease associated native or foreign genes, gene therapy approaches look increasingly promising for treating human diseases, including cancer and AIDS. To avoid bottle-necks, rapid progress needs to be made in developing efficient gene transfer vectors. Banking on our considerable expertise in human lentivirus (HIV-1 and HIV-2)gene expression and regulation, we are designing vector system derived from these retroviruses. HIV, especially HIV-2 as a vector, has the distinct advantage of targeted gene delivery, regulated expression, and non- dividing cell transduction, including stem cells. To delineate parameters governing expression and packaging, a series of HIV-2-based vectors were constructed containing the long terminal repeats (LTR) for inducible expression, gag sequences for packaging efficiency, drug resistance genes for marker selection, and those containing split hemi- genomes with selection markers for packaging with little or no helper virus production. Studies with these vectors have provided insights for identifying unique combination of transfer vectors and packaging cell lines for efficient gene transfer in human cells. Our observation that HIV-2 can downmodulate HIV-1 without reciprocal effect of HIV-1 on HIV-2 - consistent with the notion of HIV-2 provided protection against HIV-1 infection in populations at risk - provides added incentive to develop HIV-2 based retroviral vectors for gene therapy. Our report identifying beta-chemokines as here-to-for mysterious CD8 anti-HIV factors opened new vista for understanding HIV infection, disease progression and means of its control. It also contributed to the discovery of the use by HIV of chemokine receptors as co-receptors - CCR5 by M-tropic (early) and CXCR4 by T-tropic (late) viruses, with the corresponding ligands, beta-chemokines and alpha-chemokines, being the respective anti-HIV effectors. Using eukaryotic expression systems (thus more native milieau) to express recombinant chemokines, and focussing on their defined structural elements (flexible coils, beta sheets and alpha helix), domain mapping studies revealed some elements necessary and others dispensable for antiviral activity. Unexpectedly, mutational analysis has uncovered regions of the chemokine molecule critical for its stability, prompting the hypothesis of the existance of epitopes targeted by proteosomes and emphasizing the importance of proper folding. The design of a chemokine molecule composed of minimal functional domains of alpha- and beta-chemokines directed against both M- and T-tropic HIVs but without being agonist or antagonist of chmotaxis remains a viable option.